The present invention relates to a method of diagnosing whether a subject with no known history of atrial fibrillation is suffering from atrial fibrillation or not, said method comprising the steps of a) determining the amount of a BNP-type peptide in a sample of said subject; b) comparing the amount of the BNP-type peptide to a reference, and c) assessing intermittent ECG recordings obtained from said subject over a period of at least one week by using a handheld ECG device.
Atrial fibrillation (AF) is the most common type of heart arrhythmia and one of the most widespread conditions among the population. AF is characterized by irregular heart beating and often starts with brief periods of abnormal beating that can increase over time and may become a permanent condition. An estimated 2.7-6.1 million people in the United States have AF. However, many more people are likely to be affected by the condition because atrial fibrillation often comes and goes and does not always cause symptoms (Camm et al., Am J Cardiol. 2012; 110:270-6). Around a third of all atrial fibrillation patients have no symptoms and are therefore rarely discovered in routine health checks (Mozaffarian et al., Circulation. 2016; 133:e38-e360).
The diagnosis of heart arrhythmia such as atrial fibrillation typically involves determination of the cause of the arrhythmia, and classification of the arrhythmia. Guidelines for the classification of atrial fibrillation according to the American College of Cardiology (ACC), the American Heart Association (AHA), and the European Society of Cardiology (ESC) are mainly based on simplicity and clinical relevance. The first category is called “first detected AF”. People in this category are initially diagnosed with AF and may or may not have had previous undetected episodes. If a first detected episode stops on its own in less than one week, but is followed by another episode later on, the category changes to “paroxysmal AF”. Although patients in this category have episodes lasting up to 7 days, in most cases of paroxysmal AF the episodes will stop in less than 24 hours. If the episode lasts for more than one week, it is classified as “persistent AF”. If such an episode cannot be stopped, i.e. by electrical or pharmacologic cardioversion, and continues for more than one year, the classification is changed to “permanent AF”. However, episodes that last less than 30 seconds are not considered in this classification system and often remain undetected in routine health checks. The correct and early diagnosis of atrial fibrillation can thus be challenging.
The recording of the electrical activity of the heart over a period of time called electrocardiography (ECG) is essential for specific detection of heart arrhythmia and diagnosis of atrial fibrillation. However, the difficulty of diagnosing atrial fibrillation using ECG lies in the fact that the arrhythmias may occur at long intervals. Further potential symptoms such as dizziness, fainting, shortness of breath and heart palpitations may arise in a few seconds but are unspecific and disappear just as quickly, which is why they are difficult to detect with a regular resting ECG at a hospital or with a continuous ECG over a few days. The likelihood of discovering arrhythmia increases significantly when the length of the investigation can be extended and the readings are taken continuously and/or repeatedly. Handheld ECG devices allow patients to register their ECG data themselves and may be prescribed to a patient for better arrhythmia detection and management. Most of the handheld devices have simple metal contacts that the user can place their thumbs or other fingers on or place against bare skin, such as on the chest. These devices are more convenient and faster to use than the usual adhesive skin electrodes. An example of such a Handheld ECG device is the one-lead ECG recorder from Zenicor. Using this device, patients can record ECG readings by placing their thumbs on two electrodes for 30 seconds. Multiple ECG readings of 10-30 seconds may be stored or transferred to a central ECG database via a built-in mobile phone.
The device has been shown to have higher sensitivity for detection of AF than conventional 24-hour Holter recordings and has been used in a mass screening study for atrial fibrillation (Svennberg et al., Circulation 2015, Vol. 131, p. 2176-84).
An early diagnosis of atrial fibrillation is highly desired because atrial fibrillation is an important risk factor for stroke and systemic embolism (Hart et al., Ann Intern Med 2007; 146(12): 857-67; Go A S et al. JAMA 2001; 285(18): 2370-5). The most feared consequence of atrial fibrillation is (ischemic) stroke, which occurs when blood flow to the brain is blocked by a clot or by fatty deposits called plaque in the blood vessel lining. Regardless of symptomatology, the individuals with atrial fibrillation have a 5-fold increased risk of ischemic stroke (Healey et al., N Engl J Med. 2012; 366:120-9; Flaker et al., Am Heart J. 2005; 149:657-63; Friberg et al., Eur Heart J. 2007; 28:2346-53). Moreover, strokes caused by complications from AF tend to be more severe than strokes with other underlying causes. Stroke caused by atrial fibrillation gives rise to more debilitating disabilities and has a higher mortality rate. At least 30% of all stroke patients are estimated to have atrial fibrillation, so that oral anticoagulation (OAC) for stroke prevention has become a beneficial, common treatment.
Assessment of atrial fibrillation-associated stroke risk is at present mainly based on clinical risk scores such as CHADS2 and CHA2DS2-VASc (Camm et al., Eur Heart J. 2012; 33:2719-47). However, these scores provide only modest discrimination of risk for individual patients. Several biomarkers have been suggested to refine the risk assessment in atrial fibrillation for stroke outcomes and for mortality such as the cardiac biomarkers troponin and natriuretic peptides, markers of renal function, coagulation, and inflammation (Hijazi et al., Eur Heart J. 2013 May; 34(20):1475-80). The natriuretic peptides N-terminal pro brain-type natriuretic peptide (NT-proBNP), brain-type natriuretic peptide (BNP) and N-terminal pro atrial-type natriuretic peptide (NT-proANP) have been reported to be useful for the detection of paroxysmal atrial fibrillation in patients with cerebral ischemia (Wachter et al., PLOS one 2012; 7: e34351).
A stroke is often a disaster for those affected. A third of all those who have had a stroke die, and a further third are severely disabled for life. In addition, stroke is one of the diseases that results in the highest medical costs. The estimated direct medical cost of stroke in 2011 to 2012 (average annual) was $33.0 billion (MEPS, NHLBI tabulation). Between 2012 and 2030, total direct medical stroke-related costs are projected to triple, from $71.6 billion to $184.1 billion, with the majority of the projected increase in costs arising from those 65 to 79 years of age (Mozaffarian et al., Circulation. 2016; 133:e38-e360). Many of these cases can be prevented if atrial fibrillation is diagnosed and treated at an early stage. The most important treatment for stroke prevention in atrial fibrillation is anticoagulant medication, which strongly reduces the risk of stroke. People older than 75 years have a 25% risk for stroke during a five-year period. Anticoagulation treatment can prevent about 70% of strokes, if it is prescribed. In recent years new anticoagulants have been launched on the market as an alternative to traditional vitamin K antagonist treatment. Stroke prevention in cases of atrial fibrillation and primary population screening to identify individuals with low risk for stroke have been highlighted as an issue of priority. Early identification of AF could be beneficial as a stroke-preventive measure, since initiation of protective OAC treatment can be made. Opportunistic screening for AF using pulse-palpation is now recommended above age 65 according to the latest European Society of Cardiology's guidelines (Fitzmaurice et al., Bmj. 2007; 335:383), and has a detection rate of new AF of 1.6% (Lowres et al., Thromb Haemost. 2013; 110:213-22).
Screening for AF using “one-off” 12-lead ECG has in a meta-analysis identified new AF in 1.4% of >65 year olds (Lowres et al., Thromb Haemost. 2013; 110:213-22). In the systematic screening study STROKESTOP, a total of 7,173 individuals aged 75/76 years in two Swedish regions were prospectively screened for silent AF using intermittent ECG recordings for two weeks. This yielded 3% individuals with newly detected AF (NDAF), and increased the AF prevalence by more than 30% (Svennberg et al., Circulation. 2015: Vol. 131, p. 2176-84).
N-terminal prohormone of brain natriuretic peptide (NT-proBNP) is an established biomarker, clinically used mainly as a biomarker of cardiac dysfunction and fluid overload in congestive heart failure. More recently NT-proBNP has in several large cohort studies emerged as an independent predictor for incipient AF (Folsom et al., Stroke. 2013; 44:961-7; Patton et al., Circulation. 2009; 120:1768-1774; Patton et al., Heart. 2013; 99:1832-6; Schnabel et al., Circulation. 2010; 121:200-7; Okada et al., Eur J Neurol. 2010; 17:326-31; Seegers et al., Open Heart. 2015; 2:e000182).
In addition patients with AF and a high level of NT-proBNP have a higher risk of stroke (Hijazi et al., Circulation. 2012; 125:1605-16; Hijazi et al., J Am Coll Cardiol. 2013; 61:2274-84). NT-proBNP has also been shown to be associated with cardio embolic stroke (Llombart et al., B-Type Natriuretic Peptides Help in Cardioembolic Stroke Diagnosis: Pooled Data Meta-Analysis. Stroke. 2015; 46:1187-95). If screening for atrial fibrillation would occur only in individuals with a high level of NT-proBNP some individuals with AF might be missed because of unclear cutoffs a priori, but these might be the individuals with a lower risk of stroke. Furthermore, NT-proBNP levels have been reported to be higher in women than in men in previous studies (Fradley et al, Am J Cardiol. 2011; 108:1341-5; Redfield et al., J Am Coll Cardiol. 2002; 40:976-82). Heavier subjects with higher BMI are more likely to have AF (Wang et al., Jama. 2004; 292:2471-7), but prior studies have also shown an inverse relation between obesity and NT-proBNP (Rivera et al, Eur J Heart Fail. 2005; 7:1168-70; Das et al., Circulation. 2005; 112:2163-8).
A report from the Swedish government agency of Dental and Pharmaceutical Benefits, TLV has recently been published showing that screening for atrial fibrillation using intermittent ECG recordings is cost-effective (Tandvårds-ochläkemedelsförmånsverket. Kunskapsunderlag: Hälsoekonomisk utvärdering gällande primärpreventiv screening av förmaksflimmer med tum-EKG. 2014; http://www.tlv.se/Medicinteknik/Medicinteknikuppdraget/ayslutadehalsoekonomiska-bedomningar/TLV-utvarderar-tum-EKG; 2015 May 29) based on a health-economy study (Aronsson et al., Europace. 2015; 17:48-55). There might also be potential con-founders such as renal failure, as individuals with chronic renal failure have an increased risk of AF (Alonso et al., Circulation. 2011; 123:2946-2953) and higher NT-proBNP (Wang et al., Semin Dial. 2012; 25:326-33).
WO 2014/072500 discloses means and methods for diagnosing a recent paroxysmal atrial fibrillation in a subject, comprising determining the amount of at least one marker selected from the group consisting of a cardiac Troponin, a BNP-type peptide, hsCRP (high sensitive CRP), IL-6 (Interleukin-6) and IGFBP7 (Insulin like growth factor binding protein 7) in a sample from the subject.
An oral presentation was made by Prof. Marten Rosenqvist in Cannes on Apr. 26, 2015 (at the 10th International Biomarker Workshop with 37 participants, Title: “NT-proBNP and silent atrial fibrillation—The STROKESTOP II study”). The presentation dealt with the combined assessment of NT-proBNP and intermittent ECG recordings in the general population.
The technical problem underlying the present invention can be seen as the provision of methods for complying with the aforementioned needs. The technical problem is solved by the embodiments characterized in the claims and herein below.